In this proposal, funding is requested to develop and build an advanced new commercial direct detection detector (DDD) for Electron Microscopy (EM) based on an Active Pixel Sensor (APS). The APS technology can be used to build very large arrays, up to at least 3.5K x 4K pixels, of very small size (5 [unreadable]m pitch) that provide excellent signal to noise ratio (above 10:1) for a single incident electron in the range of 200-400 keV. Spatial resolution of the DDD is very high (2.4 micron) enabling cryo-EM images with enough precision to solve a 3-D macromolecule structure at a very high resolution (3 [unreadable]) using a reasonable EM magnification of 50,000 (yielding 1 pixel per [unreadable]2), a significant improvement over current methods. We will work in very close collaboration with the UCSD group headed by the same P.I. (Professor Xuong Nguyen-Huu). Using another N.I.H. grant, they have made a functional 1K x 1K DDD chip with 16 analog outputs. Our work is to integrate one of these chips into a functional and easy-to-use detector system for EM, thereby establishing a foundation for a commercial detector that could revolutionize EM image data collection. A significant factor in the rapid progress made by the UCSD group in the development of the DDD has been their use of a modified JEOL, Ltd. film cassette. This has made it easy (and fast) to mount the DDD to any JEOL, Ltd. electron microscope without the need to dismount the existing bottom-mounted Charge-Coupled Device (CCD) camera, minimizing the impact of the DDD development on users of the microscope facility. Unfortunately, this also limits the current detector to use on JEOL, Ltd. microscopes. In Phase 1, we would like to design and build a Universal Mount System that would allow the use of the new DDD in a wide variety of modern electron microscopes and establish the feasibility of reducing the DDD technology to practice by prototyping a 1K x 1K system. In a future Phase II proposal, we will request funding to build a much larger size DDD system (on the order of 3.5K x 4K pixels) and address issues of scaling the technology and handling the very large amounts of data produced. If successful, this project will greatly benefit the biotechnology companies focused on the use of 3D structures of proteins, enzymes, or viruses to pioneer new drugs to cure diseases. [unreadable] [unreadable] [unreadable]